Limb ischemia

Baumgartner, L, Pieczek, A, Manor, O., Blair, R., Kearney, M., Walsh, K. et al. (1998) Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation, 97, 1114-1123. 

Takeshita, S., Pu, L.Q., Stein, L.A., Sniderman, A.D., Bunting, S., Ferrara, N. et al. (1994) Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation, 90, II228-II234. 

Tsurumi, Y., Kearney, M., Chen, D.F., Silver, M., Takeshita, S., Yang, J.H. et al. (1997) Treatment of acute limb ischemia by intramuscular injection of vascular endothelial growth factor gene. Circulation, 96, 382-388. 

Allie DE, Hebert CJ, Lirtzman MD, et al. A safety and feasibility report of combined direct thrombin and GP llb/llla inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention treating critical limb ischemia like acute coronary syndrome. J Invasive Cardiol 2005 17 427-432. 

A small study of plasmid-derived VEGF showed collateral vessel growth and improved outcome in patients with critical limb ischemia (37), In the regional angiogenesis with VEGF (RAVE) study, AdVEGF-121 was injected into the skeletal muscle of the lower extremity and safety and efficacy were compared with placebo control in patients with unilateral, severe, disabling intermittent claudication. No symptomatic or objective evidence of clinical benefit were reported at 26-week follow-up (38). 

Masaki I, Yonemitsu Y Yamashita A, et al. Angiogenic gene therapy for experimental critical limb ischemia acceleration of limb loss by overexpression of vascular endothelial growth factor 165 but not of fibroblast growth factor-2. Circ Res 2002 90(9) 966-973,... 

Cellular myogenic and angiogenic therapy in cardiac or limb ischemia... 

Higashi Y, Kimura M, Hara K, et al. Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia. Circulation 2004 109 1215-1218. 

The clinical manifestations of PAD are associated with reduction in functional capacity and quality of life, but because of the systemic nature of the atherosclerotic process there is a strong association with coronary and carotid artery disease. Consequently, patients with PAD have an increased risk of cardiovascular and cerebrovascular ischemic events [myocardial infarction (Ml), ischemic stroke, and death] compared to the general population (4,5). In addition, these cardiovascular ischemic events are more frequent than ischemic limb events in any lower extremity PAD cohort, whether individuals present without symptoms or with atypical leg pain, classic claudication, or critical limb ischemia (6). Therefore, aggressive treatment of known risk factors for progression of atherosclerosis is warranted. In addition to tobacco cessation, encouragement of daily exercise and use of a low cholesterol, low salt diet, PAD patients should be offered therapies to reduce lipid levels, control blood pressure, control blood glucose in patients with diabetes mellitus, and offer other effective antiatherosclerotic strategies. A recent position paper... 

Ouriel et al. conducted this important equally randomized trial in which I 14 patients presenting with acute lower limb ischemia (<7 days) received either catheter-directed UK or underwent surgical revascularization (22). The primary endpoints were limb salvage and survival at 12 months. The amputation-free survival rates at one year were statistically significant at 75% and 52%, respectively. Other results of Rochester Trial are summarized in Table 2. 

The STILE (Surgery versus Thrombolysis for the Ischemic Lower Extremity) Trial compared catheter-directed lysis to surgery as well as differences in outcome between rt-PA and UK (26). This study enrolled patients with acute limb ischemia as well as chronic limb ischemia. Dosages of rt-PA were initial infusion of 0.1 mg/kg/hr followed by 0.05 mg/kh/hr for 12 hours. UK was given as 250,000 IU bolus followed by 4000 lU/min for four hours and then reduced to 2000 lU/min for 36 hours. Outcomes of this trial are summarized in Tables 4 and 5. 

In patients with acute limb ischemia, there was a significant reduction in major amputation and significantly improved amputation-free survival in the lysis group. Surgical treatment fared better in chronic limb ischemic group. Detailed analysis did not demonstrate differences in efficacy and safety between UK and rt-PA, However, lysis infusion time was shorter in rt-PA group compared to UK. 

Morishita, R., Nakamura, S., Hayashi, S., Taniyama, Y., Moriguchi, A., Nagano, T., Taiji, M., Noguchi, H., Takeshita, S., Matsumoto, K., Nakamura, T., Higaki, J., and Ogihara, T. 1999. Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33 1379-1384. 

Wahlberg, E. 2003. Angiogenesis and arteriogenesis in limb ischemia. J. Vase. Surg. 38 198-203. 

Protects against lung-injury induced by limb ischemia-reperfusion [121]... 

The effect of nonfatal injuries such as a 2-hour period of bilateral hind-limb ischemia or a full-thickness scald of 20% of skin surface on the LDso of DNOC and its hyperthermic effect were evaluated in male rats (Stoner 1969). The intraperitoneal LDs° of DNOC was significantly (p<0.001) reduced from 24.8 to 26.2 mg/kg to 14 mg/kg DNOC when DNOC was given 1.5- 24 hours after either type of nonfatal injury. The authors concluded that the toxicity of DNOC was increased by previous trauma. These investigators proposed that this interaction was associated with sequential blocking of the tricarboxylic acid cycle with inhibition of citrate synthetase reaction during the early part of the response to the injury. Because DNOC acts as an uncoupler of oxidative phosphorylation, less ATP is produced. Therefore, the effects of trauma will be enhanced by an uncoupling agent such as DNOC. 

Embolism from thrombus within the cavity of an aneurysm is rare and is difficult to prove in cases where there maybe other potential sources of embolization. Intracranial aneurysms more commonly present with rupture and subarachnoid hemorrhage, whereas internal carotid artery aneurysms tend to cause pressure symptoms including a pulsatile and sometimes painful mass in the neck or pharynx, ipsilateral Horner s syndrome or compression of the lower cranial nerves. Extracranial vertebral artery aneurysms may cause pain in the neck and arm, a mass, spinal cord compression and upper limb ischemia (Catala et al. 1993). 

Hirsch AT. Critical limb ischemia and stem cell research anchoring hope with informed adverse event reporting. Circulation 2006 114 2581-2583. 

Bosch-Marce M, Okuyama H, Wesley JB, Sarkar K, Kimura H, Liu YV, Zhang H, Strazza M, Rey S, Savino L, Zhou YF, McDonald KR, Na Y, Vandiver S, Rabi A, Shaked Y, Kerbel R, LavaUee T, Semenza GL. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion following limb ischemia. Circ. Res. 2007 101 1310-1318. 

Rajagopalan S, Olin J, Deitcher S, Pieczek A, Laird J, Gross-man PM, Goldman CK, McEllin K, Kelly R, Chronos N. Use of a constitutively active hypoxia-inducible factor-1 alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients phase I dose-escalation experience. Circulation 2007 115 1234-1243. 

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